A research team led by investigators at McMaster University has identified an axonal guidance signaling pathway that cancer cells use to infiltrate the brain. The combined results of preclinical in vitro and in vivo tests evaluating either a small molecule inhibitor of the protein PTP4A2, or a newly developed CAR-T cell-based therapeutic approach against the PTP4A-ROBO1 signalling axis demonstrated increased cell survival in brain cancer models.

由麦克马斯特大学（McMasterUniversity）研究人员领导的一个研究小组已经确定了一种轴突导向信号通路，癌细胞利用该通路渗透大脑。评估蛋白质PTP4A2的小分子抑制剂或针对PTP4A-ROBO1信号轴的新开发的基于CAR-T细胞的治疗方法的临床前体外和体内测试的综合结果表明，脑癌模型中的细胞存活率增加。

ROBO1 CAR T cells eradicated tumors in 50–100% of cancer-bearing mice. The team says their research offers new hope and potential treatment strategies for glioblastoma (GBM), the most aggressive form of brain cancer, and potentially other brain malignancies..

ROBO1 CAR T细胞在50-100%的荷瘤小鼠中根除了肿瘤。该团队表示，他们的研究为胶质母细胞瘤（GBM）提供了新的希望和潜在的治疗策略，GBM是最具侵袭性的脑癌形式，也可能是其他脑部恶性肿瘤。。

“In glioblastoma, we believe that the tumor hijacks this signalling pathway and uses it to invade and infiltrate the brain,” said Sheila Singh, MD, PhD, professor with McMaster’s department of surgery and director of the Centre for Discovery in Cancer Research. “If we can block this pathway, the hope is that we can block the invasive spread of glioblastoma and kill tumor cells that cannot be removed surgically.” Singh, and Jason Moffat, PhD, head of the Genetics and Genome Biology program at The Hospital for Sick Children (SickKids) are co-senior authors of the team’s published paper in Nature Medicine, titled “Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells.” In their paper they stated “Our study identifies a promising multi-targetable PTP4A–ROBO1 signaling axis that drives tumorigenicity in recurrent GBM, with potential in other malignant brain tumors.”.

“在胶质母细胞瘤中，我们认为肿瘤劫持了这种信号通路，并利用它入侵和渗透大脑，”麦克马斯特外科教授兼癌症研究发现中心主任SheilaSingh博士说。“如果我们能够阻断这一途径，希望我们能够阻止胶质母细胞瘤的侵袭性扩散，杀死无法通过手术切除的肿瘤细胞。”Singh和Jason Moffat博士，病童医院（SickKids）遗传学和基因组生物学项目负责人，是该团队在《自然医学》（Nature Medicine）上发表的论文的共同高级作者，该论文题为“用ROBO1 CAR T细胞靶向胶质母细胞瘤的轴突导向依赖性”。他们在论文中表示“我们的研究确定了一种有希望的多靶向PTP4A-ROBO1信号轴，可驱动复发性GBM的致瘤性，并可能在其他恶性脑肿瘤中发挥作用。”。

GBM remains the most aggressive and prevalent malignant primary brain tumor in adults, the authors wrote. Treatment for the cancer has not advanced beyond surgery, chemotherapy and radiotherapy for two decades. “Unchanged since 2005, standard of care (SoC) consists of surgical resection followed by radiation therapy plus concurrent and adjuvant chemotherapy with temozolomide (TMZ)” they stated.

作者写道，GBM仍然是成人中最具侵袭性和最普遍的恶性原发性脑肿瘤。二十年来，癌症的治疗一直没有超越手术，化疗和放疗。他们表示：“自2005年以来，护理标准（SoC）没有改变，包括手术切除，然后进行放射治疗，同时使用替莫唑胺（TMZ）进行辅助化疗。”。

However, tumors often return, and patient survival is limited to only a few months..

然而，肿瘤经常复发，患者的生存期仅限于几个月。。

To discover the pathway that cancer cells use to infiltrate the brain the researchers used large-scale gene editing technology to compare gene dependencies in glioblastoma when it was initially diagnosed and after it returned following standard treatments. “… we conducted a genome-scale comparison between patient-matched pre-treatment and post-treatment GBM models at the mutational, functional genetic, transcriptomic and proteomic levels,” they explained.

为了发现癌细胞浸润大脑的途径，研究人员使用大规模基因编辑技术来比较胶质母细胞瘤最初诊断时和标准治疗后复发后的基因依赖性。“我们在突变，功能遗传学，转录组学和蛋白质组学水平上对患者匹配的治疗前和治疗后GBM模型进行了基因组规模的比较，”他们解释道。

Their analyses identified the PTP4A2-ROBO1 pathway which is involved in axonal guidance—a signalling axis that helps establish normal brain architecture —that can become overrun by cancer cells. Their combined results, they suggested “…  indicate that modulation of the PTP4A–ROBO1 axis could be a viable strategy to target rGBM and requires further mechanistic investigation and optimization of therapeutic interventions.”.

。他们的综合结果表明，“……表明调节PTP4A-ROBO1轴可能是靶向rGBM的可行策略，需要进一步的机制研究和治疗干预的优化。”。

The team evaluated different methods to prevent cancer cells hijacking this pathway, including use of a pan-PTP4A chemical inhibitor. The team also developed a CAR T cell therapy to target the signaling pathway in the brain through inhibition of ROBO1, the protein that helps guide certain cells, similar to a GPS.

。该团队还开发了一种CAR T细胞疗法，通过抑制ROBO1来靶向大脑中的信号通路，ROBO1是一种类似于GPS的蛋白质，有助于引导某些细胞。

“ROBO1 is an axonal guidance gene associated with migration and invasion of GBM cells,” they explained..

他们解释说：“ROBO1是一种与GBM细胞迁移和侵袭相关的轴突导向基因。”。。

“We created a type of cell therapy where cells are taken from a patient, edited and then put back in with a new function,” said lead author Chirayu Chokshi, PhD, who worked alongside Singh at McMaster University. “In this case, the CAR T cells were genetically edited to have the knowledge and ability to go and find ROBO1 on tumor cells in animal models.”.

“我们创造了一种细胞疗法，从患者身上提取细胞，进行编辑，然后用新功能重新植入，”首席作者Chirayu Chokshi博士说，他与辛格一起在麦克马斯特大学工作。。

Singh and Chokshi say the CAR T cell approach could also be relevant to other invasive brain cancers. In their reported study the researchers examined models for three different types of cancer including adult glioblastoma, adult lung-to-brain metastasis, and pediatric medulloblastoma. In all three models, treatment led to a doubling of survival time.

。在他们报道的研究中，研究人员检查了三种不同类型癌症的模型，包括成人胶质母细胞瘤，成人肺脑转移和小儿髓母细胞瘤。在所有三种模型中，治疗导致存活时间加倍。

In two of the three diseases therapy led to tumor eradication in at least 50% of the mice. “Our study establishes ROBO1 CAR T cells as a potent immunotherapy for GBM and other highly invasive brain cancers,” the investigators stated..

在三种疾病中的两种中，治疗导致至少50%的小鼠根除肿瘤。研究人员表示：“我们的研究建立了ROBO1 CAR T细胞作为GBM和其他高侵袭性脑癌的有效免疫疗法。”。。

“In this study, we present a new CAR T therapy that is showing very promising preclinical results in multiple malignant brain cancer models, including recurrent glioblastoma,” Singh added. “We believe our new CAR T therapy is poised for further development and clinical trials.”

辛格补充道：“在这项研究中，我们提出了一种新的CAR T疗法，该疗法在包括复发性胶质母细胞瘤在内的多种恶性脑癌模型中显示出非常有希望的临床前结果。”。“我们相信我们的新型CAR T疗法有望进一步开发和临床试验。”

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